Scientific Report NVS. Department of Neurobiology, Care Sciences and Society

Transcription

1 Scientific Report NVS Department of Neurobiology, Care Sciences and Society

2

3 Content Head of Department - Åke Seiger 4 Organization 5 Postgraduate Education 8 Tomorrow s Health Care: Basic and Advanced Level Education 8 Amyloid processes and neuroplasticity in Alzheimer s disease: Division of Alzheimer Neurobiology 10 Health in Late Life: Aging Research Center 13 Searching for mechanisms and targets: Karolinska Insitutet - Alzheimer s Disease Research Center 17 Clinical Geriatrics 24 Division of Neurodegeneration 26 Center for Family and Community Medicine 28 Seeking New Concepts: Applied Neuroendocrinology 32 Practical, Ethical and Existential: Division of Nursing 33 Teamwork: Division of Neurorehabilitation 39 Movement Science: Division of Physiotherapy 40 Nutritional Needs: Clinical Nutrition 46 Frequent Emergencies: Psychosocial Work 47 Occupational Therapy 48 Doctoral Theses Licentiat Theses Large Grants, Awards and Appointments

4 Head of Department Åke Seiger the innovative interventions of rehabilitative neurosurgery. NVS has organized the largest research network in the area of family medicine in the country, with special emphasis on migratory influences on general health, socioeconomical impact on the health of underprivileged immigrants and lifestyle factors influencing cardiovascular health parameters. NVS dominates research at KI in the area of care science. A number of research projects span from the psychosocial health of health care professionals to care of elderly and seriously ill patients. An extensive network of collaborating centers worldwide is involved in this NVS organized research. Åke Seiger, MD PhD Professor and Head of Department The Department of Neurobiology, Care Sciences and Society (NVS) has grown rapidly during my time as Head, and is now by the end of 2007 the largest department at KI. Although NVS is responsible for a substantial part of the undergraduate education at KI, research dominates the activities of the department. The researchers at NVS pursue internationally competitive research within the fields of geriatrics, family medicine, neuroscience, rehabilitation, and the health sciences. NVS was by the end of 2007 a major medical research department, with more than 200 simultaneous PhD students in education. The goal is to be nationally leading and internationally competitive wherever we are active. NVS is actively expanding and improving as a research department and it is my judgment that the department is an attractive, increasingly successful department within the KI family and with a bright future. The library at Campus Huddinge The NVS geriatric research focus is mainly on dementia and cognitive decline, and accounts for one third of clinical neuroscience research at KI. The success of this line of research is evident not only in internationally acknowledged publications, but also with regard to the establishment of two national centers of excellence: Swedish Brain Power (funded by a consortium of government coordinated foundations), and the Aging Research Center (funded by the Swedish Council for Working Life and Social Research). NVS dominates research at KI in the area of rehabilitation. The divisions of Physiotherapy, Occupational therapy and Neurorehabilitation almost exclusively analyze rehabilitative strategies for individuals with physical and neurological limitations. The research spans from biological constraints on full function to 4

5 Organization NVS is organized in divisions, with staff ranging from a few to over a hundred per division. Each division is led by a division head, typically a professor or a senior researcher, who is responsible for administration, economy, and personnel. Within the larger divisions, there are typically a number of research groups, each led by a professor or senior researcher. By the end of 2007, NVS consisted of 13 divisions. Organizational Expansion NVS has expanded between 2005 and The division of Family Medicine joined NVS in 2005, and in 2006 the divisions of Nursing, Neurorehabilitation, and Clinical Nutrition merged with NVS. of the department. These include the group of division heads, the coordination group, the advisory board, the admissions board, the work environment group, and the education committee Numbers of employees at NVS Management The Head of NVS, Åke Seiger, was appointed by the President of KI in He has two deputy heads, Kerstin Tham (as of 2003) and Agneta Herlitz (as of 2007), a financial manager (Ulf Edin), a human resources manager (Ulla Cronfalk-Hernlund), and an administrator (Siw Lundin/Anette Stålbalk) to assist him. The work of the department head is supported by a number of different bodies, shaping the policy and the standard HEAD OF DEPARTMENT DIVISIONS Aging Research Center Center for Family and Community Medicine Neurodegeneration Alzheimer Neurobiology Clinical Geriatrics Neurorehabilitation Advisory Board Applied Neuroendocrinology Clinical Nutrition Nursing Coordination Group Work Environment Group Education Committee Admissions Board Occupational Therapy KI - Alzheimer s Disease Research Center Physiotherapy Psychosocial Work 5

6 Human Resources By the end of 2007, there were close to 500 persons employed at NVS, of which 23 are professors, 90 senior researchers or senior lecturers, and 146 lecturers. In addition, there are approximately 200 doctoral students enrolled. The human resource department works both strategically and operationally in the fields of leadership training, recruitment, rehabilitation, work environment, health promotion, and salary administration. partment has grown both in revenue and in number of employees. The ratio between research and education, in terms of revenue and costs, is approximately 55/45. Between 2005 and 2007, research revenue increased by approximately 10%. Together with the Stockholm County Council, the Japanese company Dainippon Sumitomo Pharmaceuticals is by far the largest external contributor to research at the department with a total contribution of almost SEK 20 million per year between 2005 and The Nine Major Contributors to NVS Research Human resource manager Ulla Cronfalk-Hernlund Staff at NVS Female Male Total Administrative staff Other/technical staff Doctoral students Postdocs Junior researchers Senior researchers Lecturers Senior lecturers Professors Total MSEK Government base funding Dainippon Sumitomo Pharmaceuticals Stockholm County Council (SLL) Swedish Council for Working Life and Social Research (FAS) Swedish Research Council (VR) European Union (EU) The Swedish Governmental Agency for Innovation Systems (Vinnova) Knut and Alice Wallenberg Foundation Stiftelsen Stockholms Sjukhem Total departmental research budget 338,005 MSEK Funding At NVS there are many successful researchers, teachers, and other personnel groups that provide the basis for a positive development. The department has over the years continuously increased both governmental and external research grants. Since the year 2000, the de- Financial manager Ulf Edin 6

7 Management: Agneta Herlitz, Åke Seiger, Kerstin Tham, Ulla Cronfalk-Hernlund, Ulf Edin and Anette Stålbalk Divisions Heads: (top row) Lars-Erik Strender, Karin Harms-Ringdahl, Agneta Nordberg, Torkel Falkenberg, Lars-Olof Wahlund, Angel Cedazo-Minguez, (bottom row) Marti Parker, Lena Nilsson-Wikmar, Kerstin Tham, Gerd Faxén-Irving, Anders Kottorp, Erik Sundström 7

8 Postgraduate Education Of about two hundred active postgraduate students, 95 percent were registered for a doctoral degree and 5 percent for a licentiate degree. Women make up 79 percent of the student population. In the years 2005 through 2007, ninety students defended their theses and received a doctor s degree. An additional six students received licentiate degrees. Applications for admittance to postgraduate studies are evaluated by an admissions board comprised of faculty members of the department and a PhD student representative. The application consists of a written document and a seminar. There are two application dates per semester and a registration seminar about four weeks after each deadline. The seminar is given in English and the project is discussed with the supervisors and the student. The admissions board is lead by the director of postgraduate studies or one of the two vice directors. Research at the department ranges from molecular biology to clinical studies and care research, and the directors of postgraduate education are chosen to have expertise in these areas. The department head and the postgraduate education director meet the PhD student representatives once a month for information and discussion about the postgraduate education. Several postgraduate courses are organized by NVS scientists. Journal clubs and PhD student seminars are also part of the postgraduate education. Once a year all postgraduate students are required to submit a yearly update report on the advancement of their studies, and twice a year they submit an activity report. All new supervisors are required to take a supervisor course at Karolinska Institutet. Tomorrow s Health Care: Basic and Advanced Level Education One third of all students enrolled in basic and advanced level training at Karolinska Institutet belong to NVS. Tomorrow s health care personnel, researchers, and teachers are trained in an environment of specialist medical care and internationally recognized research. Development of education. NVS is developing a unique profile in higher education at the basic and advanced levels. For example, our experience and competence are unique in distance learning and interprofessional education. All education is closely linked to research, and we have a strategy of involving external collaborators such as foreign and Swedish technical universities, clinical institutions, and communities. Vocational education. Our department is home to three vocational programs at basic levels: nursing, physiotherapy, and occupational therapy. All advanced level specialist nurses training also takes place here. Medical students take courses in, for example, family medicine and geriatrics, and psychology students take courses in cognitive and developmental psychology. One-year and two-year master s courses. Master s courses at an advanced level are a part of the new European university education. In Sweden there are one- and two-year master s courses of 240 credit hours intended to enhance academic skills and confer qualification for research training. The one- and two-year master s courses in clinical medical science are interprofessional and include skills relating to prevention, care, and rehabilitation/habilitation in various forms for both individuals and groups, as well as skills in coordination and cooperation across professional boundaries to reinforce teamwork. Students are also given the opportunity to conduct joint research-oriented projects. 8

9 Education at the Division of Nursing 9

10 Amyloid processes and neuroplasticity in Alzheimer s disease: Division of Alzheimer Neurobiology Our most common neurodegenerative disorder, Alzheimer s disease (AD), afflicts 26 million people worldwide. The intense research of past decades has found no cure, and the underlying pathological mechanisms that initiate the disease remain obscure. Our research aims to grasp new and important knowledge about the cellular processes underlying neuropathological changes in Alzheimer s disease. We investigate why amyloid accumulation starts in the brain and how this relates to inflammatory processes, nerve cell communication, plasticity, and regenerative processes in the brain. We need to develop early diagnostic tools and effective treatment of AD, but our ultimate goal is to find a cure for this devastating disease. Our translational approach bridges experimental studies in cells and transgenic mice models with clinical studies in AD patients and subjects at risk of developing AD. Our pioneering development of amyloid imaging in the brains of AD patients makes use of 11 C-PiB, and positron emission tomography (PET). We found a robust difference between the amyloid load of AD patient brain and healthy controls. In a two-year follow-up study, a cohort of 15 AD patients underwent a second scanning procedure. We demonstrated a stable amyloid load in the human brain despite a decline in the cerebral glucose metabolism and cognitive function. We were also able to show high amyloid levels in PiB images of patients with mild cognitive impairment (MCI) who later converted to AD. Nonconverting MCI patients showed low amyloid loads as measured by PiB. These findings suggest the time course of amyloid Division head Agneta Nordberg deposition in the human brain may differ from changes in functional activity in the cerebral glucose metabolism of the brain and cognitive function. A maximal amyloid load may be reached at a very early prodromal state of AD. PET imaging shows that cortical 11 C-nicotine binding correlates with the cognitive function of attention in Alzheimer patients. A significant correlation has also been observed between butyrylcholinesterase activity Images of PIB retention (amyloid) and FDG uptake (glucose metabolism) for one healthy control, one AD patient with baseline and follow-up images, one MCI patient that has not converted to AD and one MCI patient that converted to AD 13 months after the PET examination. Picture courtsey from Uppsala PET center/karolinska University Hospital, Stockholm, Sweden 10

11 (a) Human neural stem cells cultured in serum-free media differentiate into neurons (green) and (b) astrocytes (red). Human stem cells transplanted into AD transgenic mice brain differentiate into mostly glial cells, which surround the amyloid plaques (c). Modification of the brain environment in these mice such as reducing amyloid by drug treatment, prior to transplantation induces increased neurogenesis of transplanted cells (d). (BuChE)in cerebrospinal fluid (CSF) and the cortical cerebral glucose metabolism. We used a multitracer PET approach to measure brain glucose metabolism ( 18 F-FDG), nicotinic receptor density ( 11 C-nicotine), and acetylcholinesterase activity ( 11 C-PMP) in mild AD patients and investigate the symptomatic effect of drugs currently being used, including rivastigmine and galantamine. Patients treated with galantamine were studied using PET and demonstrated a decrease in cortical acetylcholinesterase (AChE) activity that was comparable with the inhibition measured in cerebrospinal fluid (CSF). Rivastigmine caused an increase in nicotinic receptors following 3 months of treatment. No effect on nicotinic receptors was observed in the brain following treatment with galantamine for similar lengths of time in AD patients. A significant positive correlation was observed between changes in cortical nicotinic receptors and attentional tests of AD patients following 12 months of treatment with rivastigmine and galantamine. The multitracer PET method demonstrates the importance of evaluating the mechanisms of action and efficacy in new AD treatments. Transgenic amyloid precursor protein (APP) mice 11 models provide a further understanding of amyloid processes in the brain, but they do not represent a true model of AD. They may prove invaluable in the study of an isolated feature of the disease. High Aß production has been found in the brains of transgenic APP mice from birth, most of it a soluble form of Aß, which causes changes in the levels of the synaptic marker synaptophysin, α7-nicotinic receptors, and NMDA receptors. Nicotine treatment effectively reduces insoluble Aß 1-40 and Aß 1-42 by 50 percent in 10-month-old AD transgenic mice. This effect was not observed in mice treated with memantine or galantamine. Similar nicotine treatment in transgenic AD mice crossed with AChE overexpressing mice (resulting in a heavier Aß load) showed no effect on Aß levels. The number of astrocytes around the plaques was reduced following nicotine treatment in both transgenic mice ßmodels, probably as a consequence of the anti-inflammatory effect of nicotine. A highly challenging objective is to understand the mechanisms of the intrinsically neurogenic and/or regenerative processes of the aging brain. This objective has a vast potential in AD, where therapeutic ma-

12 nipulation of endogenous neurogenesis may not only be feasible but necessary to reverse the course of the disease. In collaboration with Professor Outi Hovatta of Karolinska Institutet, we initiated studies on human embryonic human stem-cell (hes) lines. We successfully generated radial glia cells from hes and promoted differentiation in hes by using neurotrophic factors to cholinergic cells expressing functional cholinergic receptors. In a most recent cutting edge study, we showed that the novel drug phenserine by affecting the APP/Aß cascade could increase neurogenesis and augment the survival of transplanted stein cell-derived neurosis in the brain of Alzheimer transgenic mice. Using PET, we recently observed with great interest a decrease in the Aß load (PiB retention) of AD patient brains following phenserine treatment. These studies are promising for the development of new anti-amyloid therapy strategies in AD. Darreh-Shori T, Kadir A, Almkvist O, Grut M, Wall A, Blomquist G, Eriksson B, Langstrom B, Nordberg A. Inhibition of acetyl cholinesterase in CSF versus brain assessed by (11)C-PMP PET in AD patients treated with galantamine. Neurobiol Aging Dec 28 [Epub ahead of print]. 2008;29: Engler H, Forsberg A, Almqvist O, Blomquist G, Larsson M, Savitcheva I, Wall A, Ringheim A, Långström B, Nordberg A. Two-year follow-up for amyloid deposition in patients with Alzheimer s disease. Brain. 2006;129: Forsberg A, Engler H, Almkvist O, Blomquist G, Hagman G, Wall A, Ringheim A, Långström B. Nordberg A. PET imaging of amyloid deposition in patients with mild cognitive impairment. Neurobiol Aging May 10 [E-pub ahead of print]. 2008;29: Kadir A, Darreh-Shori T, Almkvist O, Wall A, Långström B, Nordberg A. Changes in brain (11C)-nicotine binding sites in patients with mild Alzheimer s disease following rivastigmine treatment as assessed by PET. Psychopharmacology (Berl). 2007;191: Marutle A, Ohmitsu M, Nilbratt M, Greig NH, Nordberg A, Sugaya K. Modulation of human neural stem cell differentiation in Alzheimer (APP23) transgenic mice by phenserine. Proceedings National Academy of Sciences. 2007;104: Division of Alzheimer Neurobiology: Selected publications Celsi F, Svedberg M, Unger C, Cotman CW, Carri MT, Otterssen OP, Nordberg A, Torp R. Beta-amyloid causes downregulation of calcineurin in neurons through induction of oxidative stress. Neurobiol Dis Jan 25 [Epub ahead of print]. Darreh-Shori T, Brimijoin S, Kadir A, Almkvist O, Nordberg A. Differential CSF butyrylcholinesterase levels in Alzheimer s disease patients with the ApoE e4 allele, in relation to cognitive function and cerebral glucose metabolism. Neurobiol Dis. 2006;24: Darreh-Shori T, Meurling L, Pettersson T, Hugosson K, Hellström- Lindahl E, Andreasen N, Minthon L, Nordberg A. Changes in the activity and protein levels of CSF acetylcholinesterases in relation to cognitive function of patients with mild Alzheimer s disease following chronic donepezil treatment. J Neural Transmission. 2006;113: Engler H, Santillo A, Lindau M, Savitcheva I, Nordberg A, Lannfelt L, Långström B, Kilander L. In vivo amloid imaging with PET in frontotemporal dementia. Eur J Nucl Med and Molec Imaging. 2007;36: Francis PT, Nordberg A, Arnold SE. A preclinical view of cholinesterase inhibitors in neuroprotection: do they provide more than symptomatic benefits in Alzheimer s disease? Trends in Pharmacological Science. 2005;26: Hedberg MM, Svedberg MM, Mustafiz T, Yu WF, Mousavi M, Guan ZZ, Unger C, Nordberg A. Transgenic mice overexpressing human acetylcholinesterase and the Swedish APP mutation - effect of nicotine treatment. Neuroscience Nov 29 [Epub ahead of print]. 2008;152: Johansson A, Savitcheva I, Forsberg A, Engler H, Långström B, Nordberg A, Askmark H. 11C-PIB imaging in patients with Parkinson s disease. Parkinsonism and related disorders Sep 11 [Epub ahead of print]. 2008;14: Kadir A, Almkvist O, Wall A, Långström B, Nordberg A. PET imaging of cortical 11C-nicotine binding correlates with the cognitive function of attention in Alzheimer s disesease. Psychopharmacology. 2006;188: Kadir A, Darreh-Shori T, Almkvist O, Wall A, Grut M, Strandberg B, Ringheim A, Eriksson B, Blomquist G, Långström B, Nordberg A. PET imaging of the in vivo acetylcholinesterase activity and nicotine binding in galantamine-treated patients with AD. Neurobiology of Aging [E-pub ahead of print]. 2008;29: Nat R, Nilbratt M, Narkilahti S, Winblad B, Hovatta O, Nordberg A. Neurogenic neuroepithelial and radial glial cells generated from six human embryonic stem cell lines in serum-free suspension and adherent cultures. Glia. 2007;55: Nordberg A. Amyloid imaging in Alzheimer s disease. Current Opinion in Neurology. 2007;20: Stefanova E, Wall A, Almkvist O, Nilsson A, Forsberg A, Långström B, Nordberg A. Longitudinal PET evaluation of cerebral glucose metabolism in rivastigmine treated patients with mild Alzheimer s disease. J Neural Transm. 2006;113: Unger C, Hedberg MM, Mustafiz T, Svedberg MM, Nordberg A. Early changes in Ab levels in the brain of APPswe transgenic mice Implication on synaptic density, a7 neuronal nicotinic acetylcholine- and N-methyl-D-aspartate receptor levels. Mol Cell Neurosci. 2005;30: Unger C, Svedberg MM, Yu WF, Hedberg MM, Nordberg A. Effect of subchronic treatment of memantine, galantamine, and nicotine in the brain of Tg2576 (APPswe) transgenic mice. J Pharmacol Exp Ther. 2006;317: Yu WF, Guan ZZ, Bogdanovic N, Nordberg A. High selective expression of alpha 7 nicotinic receptors on astrocytes in the brains of patients with sporadic Alzheimer s disease and patients carrying Swedish APP 670/671 mutation: a possible association with neuritic plaques. Exp Neurol. 2005;192:

13 Health in Late Life: Aging Research Center Sweden s population is one of the oldest in the world. What are the needs of the eldest sector of the population? Why are most elderly people healthy, while others have multiple chronic conditions? Why do some people become demented in old age? What factors from earlier in life are associated with health and cognition in later life? These are some of the questions explored by researchers at the Aging Research Center (ARC). The ARC was established in 2000 through the initiative of the Swedish Council for Working Life and Social Research (FAS). The ARC is a multidisciplinary research center administered by Karolinska Institutet in collaboration with Stockholm University. A board of representatives from FAS and both universities guides the Center s work. The ARC is organized into three sectors: geriatric medicine, psychology, and social gerontology. Working closely with the Stockholm Gerontology Research Center and the Swedish Dementia Centre, the ARC disperses research results to people working in the field and the general public. Primary goals are to carry out and support high-quality aging research from a medical, psychological, and social perspective. The ARC advances multidisciplinary efforts in research on aging, offers graduate students a high-quality education in a stimulating environment, fosters collaboration with aging researchers in Sweden and abroad, develops cross links between available data sets, and directs the acquired knowledge into interventions. Most ARC research is based on quantitative analysis of population-based data from interview surveys and examinations. Research is also based on psychological tests, brain imaging (PET, fmri), and genetic testing. New Analytical Strategies: Geriatric Epidemiology Laura Fratiglioni, Johan Fastbom, Eva von Strauss, Miia Kivipelto The risk factors of Alzheimer s disease (AD) and other dementia disorders are one of the five major lines of research. The other four lines study mild cognitive impairment (occurrence, risk factors and progression); disability, multimorbidity and longevity; pharmacoepidemiology; and health economy. We use several longitudinal databases, including the SNAC-K, the Kungsholmen Project, the twin study HARMONY, and the Finnish CAIDE study. In addition, international collaborations have lead to interesting reports concerning the impact of dementia worldwide, the relevance of cerebrovascular disorders, and new analytical strategies to detect early symptoms of AD. Some of the risk factors found for dementia include anemia, heart failure, and low diastolic blood pressure, confirming our hypothesis that low chronic hypoperfusion in the brain may increase risk of cognitive deterioration. We have detected a clear association of borderline diabetes and several vascular risk factors at middle age with AD. Several studies using different cohorts, including the twin study, have suggested that midlife physical activities and higher education are protective factors. Cognitive impairment is a common condition in the elderly population, due to multiple causes. Not only the AD-type neurodegenerative process, but also neuropsychiatry and frailty-related factors may induce cognitive impairment in nondemented elderly persons. Anxiety symptoms may be a reliable predictor of progression to dementia. More than 50 percent of the persons aged 75 and more are affected by multimorbidity. Low education increases the risk of multimorbidity, suggesting that unhealthy behaviors linked to educational level or socioeconomic status in early life may still play a role in the health status of the very old. Studying the genetic background for multimorbidity and longevity, a different role of the apoe alleles in survival by gender in old age has been detected. Some of the students and researchers at ARC Studies of pharmacoepidemiology are utilizing a new 13

14 nationwide drug register. Swedish persons over 75 years use an average of 5.4 drugs. There are wide differences between counties in regards to inappropriate drug use. Finally, informal and formal care was examined using the resource utilization in dementia (RUD) instrument. The amount of informal care was greater than formal care; informal care was more common among demented persons. Analysis suggested that informal care tends to substitute formal care for persons with dementia. Atti AR, Palmer K, Volpato S, ZulianiG, Winblad B, Fratiglioni L. Anaemia increases the risk of dementia in cognitively intact elderly. Neurobiol Aging. 2006; 27: Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, Hall K, Hasegawa K, Hendrie H, Huang Y, Jorm A, Mathers C, Menezes PR, Rimmer E, Scazufca M, Alzheimer s Disease International. Global prevalence of dementia: a Delphi consensus study. Lancet. 2005;366: Gatz M, Reynolds CA, Fratiglioni L, Johansson B, Berg S, Fiske A, Pedersen NL. The role of genes and environments for explaining Alzheimer s disease. Arch Gen Psychiatry. 2006;63: Qiu C, Winblad B, Fratiglioni L. The age-dependent relation of blood pressure to cognitive function and dementia. Lancet Neurol. 2005;4: Qiu C, Winblad B, Marengoni M, Fastbom J, Fratiglioni L. Heart failure and the risk of Alzheimer s disease and dementia: a population-based prospective study. Arch Intern Med. 2006;166: Cognitive Performance: Psychology Lars Bäckman, Håkan Fischer, Agneta Herlitz We look at the cognitive changes occurring in normal and pathological aging. The effects of individual-difference variables such as health, gender, and hormones on cognitive functioning is another focus, along with the biological basis of age-related cognitive changes, and whether older persons improve cognitive performance following intervention. A major theme is the identification of persons at risk for dementia many years before clinical diagnosis. Key findings are that the preclinical period in Alzheimer s disease (AD) spans at least a decade and involves deficits in multiple domains (e.g., episodic memory, speed, executive functioning). Interestingly, AD patients and patients with vascular dementia exhibit similar patterns of preclinical cognitive deficits, despite etiological differences. Furthermore, the well-known terminal-decline phenomenon is largely attributable to preclinical dementia. We use fmri to delineate neural correlates of cognitive functioning across the life span, and PET to determine markers of the dopamine (DA) systems. There appears to be an aging-related shift from medial-temporal (amygdala) to frontal regions during both perception and successful encoding of emotional information. In addition, both pre- and postsynaptic age losses in dopaminergic neurotransmission contribute to cognitive deficits in old age. Graduate students and researchers in the Psychology group: Petra Thilers, Yvonne Brehmer, Floortje Smeets, Anna Rickmann, Håkan Fischer, Agneta Herlitz, Sari Karlsson, Johanna Lovén och Åsa Livner. Missing in the picture are Lars Bäckman, Jenny Rehnman, Erika Jonsson Laukka and Stuart MacDonald. 14

15 Participant in the longitudinal SNAC-K project. Contrary to common beliefs, there is little support for the view that cognitive performance is affected by testosterone or estrogen. For example, there are no cognitive differences among premenopausal, perimenopausal, and postmenopausal women. Furthermore, the cognitive sex differences seen in childhood and adulthood remain in late life, unaffected by the biological and psychological factors associated with the aging process. Cognitive intervention studies have involved training in mnemonic strategies to improve memory for verbal and numerical information. There are marked trainingrelated gains in old age. However, transfer to untrained tasks is sparse and gains are largest for advantaged older adults (in terms of education). Although improvement from cognitive interventions is considerable in aging, young adults improve even more. We have linked this age-related reduction in cognitive reserve to failure to recruit relevant frontal and hippocampal regions in response to training. Bäckman L, Jones S, Berger AK, Jonsson Laukka E, Small BJ. Cognitive impairment in preclinical Alzheimer s disease: a meta-analysis. Neuropsychology. 2005;19: Bäckman L, Nyberg L, Lindenberger U, Li SC, Farde L. The correlative triad among aging, dopamine, and cognition: current status and future prospects. Neurosci Biobev Rev. 2006;30: Gerstorf D, Herlitz A, Smith J. Stability of sex differences in cognition in advanced old age: The role of education and attrition. J of Gerontology Series B: Psychological Sciences and Social Sciences. 2006;61B: Herlitz A, Thilers P, Habib R. Endogenous estrogen is not associated with cognitive performance before, during, and following menopause. Menopause. 2007;14: MacDonald SWS, Nyberg L, Bäckman L. Intraindividial variability in behavior: Links to brain structure, neurotransmission, and neuronal activity. Trends Neurosci. 2006;29: Pathways: Social Gerontology Mats Thorslund, Marti Parker, Ingemar Kåreholt The process of human aging must be studied in a social context. Understanding the social pathways that determine health in late life will help us anticipate future needs and challenges in care services. The primary focus of our work has been to describe diversity among elderly people and to analyze associations between various dimensions of health and social factors such as socioeconomic position, marital status, and gender. Longitudinal data starting from 1968 (the Level of Living Studies and the Swedish Panel Study of Living Conditions of the Oldest Old, allow us to study how differences have developed over time and to study their cumulative effects over the life course. We strive to identify risk factors for disease and poor function as well as to identify protective factors correlated with good health in old age. The effect of risk and pro- 15

16 tective factors can differ for men and women and for different social classes. Our findings are important in developing social policy for the aging population and to compensate for social inequalities through social services, economic support, or health care. Major findings Analyses of population health show improvements from 1980 into the mid- 1990s, after which change is mixed, with some health indicators showing worse health. Mortality analyses from 1992 and 2002 show improved mortality over time, with the greatest improvement among men with very poor health. Yet another study explored health inequalities between 1991/92 and 2000/02 and showed a persistent social gradient in health: individuals who had held lower socioeconomic positions were more likely to experience a range of health problems in old age. Analyses of participation in leisure time activities showed increased participation among later cohorts and that people who are more active in middle age had a lower risk for cognitive impairment in old age. Agahi N, Ahacic K, Parker MG. Continuity of leisure participation from middle age to old age. J Geron: Soc Sci. 2006:61B: Andel R, Kåreholt I, Parker MG, Thorslund M, Gatz M. Complexity of primary lifetime occupation and cognition in advanced old age. J Aging Health. 2007;19: Meinow B, Parker MG, Kåreholt I, Thorslund M. Complex health problems in the oldest old in Sweden Eur J Ageing. 2006;3: Parker M, Ahacic K, Thorslund M. Health changes among Swedish oldest old: prevalence rates from 1992 and 2002 show increasing health problems. J Gerontol A Biol Sci Med Sci. 2005;60: Parker MG, Thorslund M. Health trends in the elderly population: getting better and getting worse. Gerontologist. 2007;47: Aging Research Center: Selected publications Agahi N, Parker MG. Are today s older people more active than their predecessors? Participation in leisure-time activities in Sweden in 1992 and Ageing & Society. 2005:25: Fischer H, Sandblom J, Nyberg L, Herlitz A, Bäckman L. Brain activation while forming memories of fearful and neutral faces in women and men. Emotion 2007;7: Fors S, Thorslund M, Parker MG. Do actions speak louder than words? Self-assessed and performance-based measures of physical and visual function among old people. Eur J Ageing. 2006;3: Johnell K, Fastbom J, Rosén M, Leimanis A. Inappropriate drug use in the elderly: a nationwide register-based study. Ann Pharmacother. 2007;41: Jones S, Livner Å, Bäckman L. Patterns of prospective and retrospective memory impairment in preclinical Alzheimer s disease. Neuropsychology. 2006;20: Jonsson Laukka E, MacDonald SWS, Bäckman L. Contrasting cognitive trajectories of impending death and preclinical dementia in the very old. Neurology. 2006;66: Karp A, Paillard-Borg S, Wang HX, Silverstein M, Winblad B, Fratiglioni L. Mental, physical and social components in leisure activities equally contribute to decreased dementia risk. Dement Geriatr Cogn Disord. 2006;21: Larsson K, Silverstein M, Thorslund M. Delivering care to older people at home. In:Johnson M, editor. The Cambridge Handbook of Age and Ageing. Cambridge: Cambridge University Press; p Larsson K, Thorslund M. Old peoples s health. Scand J Public Health. 2006;34: Lennartsson C, Lundberg O. What s marital status got to do with it? Gender inequalities in economic resources, health and functional abilities among older adults. In: Fritzell J, Lundberg O, editors. Health Inequalities and Welfare Resources: Continuity and Change in Sweden. Brighton: Policy Press; MacDonald SWS, Derwinger A, Stigsdotter Neely A, Bäckman, L. Rate of acquisition, adult age, and basic cognitive abilities predict forgetting: new views on a classic problem. J Exp Psychol Gen. 2006;135: Palmer K, Berger AK, Monastero R, Winblad B, Bäckman L, Fratiglioni L. Predictors of progression from Mild Cognitive Impairment to Alzheimer s Disease. Neurology. 2007;68: Thilers P, MacDonald SWS, Herlitz A. The effect of endogenous free testosterone on cognitive performance: a population-based study in 35 to 90 year old men and women. Psychoneuroendocrinology. 2006;31: Xu WL, Qiu CX, Winblad B, Fratiglioni L. The effect of borderline diabetes mellitus on the risk of dementia and Alzheimer disease. Diabetes. 2007:56: Kivipelto M, Ngandu T, Laatikainen T, Winblad B, Soininen H, Tuomilehto J. Risk score for prediction of dementia risk in 20 years among middle aged people: a longitudinal population based study. Lancet Neurology. 2006;9:

17 Searching for mechanisms and targets: Karolinska Institutet-Alzheimer s Disease Research Center At the Alzheimer s Disease Research Center at Karolinska Institutet (KI-ADRC) we investigate the mechanisms behind Alzheimer s disease (AD). AD is the most common form of dementia in the aging population. Known risk factors for the development of AD include increasing age, genetic factors, and environmental factors. Diagnostic markers (CSF and imaging) for early diagnosis have been developed and are undergoing validation. Symptomatic drug treatment is currently available, but a number of trials are under way for disease modifying treatment. Many of us work in the Karolinska Institutet Dainippon Sumitomo Pharma Center (KASPAC), together with the Japanese company Dainippon Sumitomo Pharma, to identify novel targets for AD therapeutics. We have been collaborating for eight years, currently until August Also, we coordinate a national network called Swedish Brain Power (SBP). SBP is a joint program funded by several private research funds and governmental institutions to strengthen innovative research and cooperation among academia, industry, and health care. Both KI-ADRC (including KASPAC) and SBP are directed by Bengt Winblad. At the KI-ADRC, we aim to contribute to the understanding of the cellular, metabolic, and molecular changes that induce AD pathology and help define new biomarkers and therapeutic markers for the disease. Some examples of the research performed at KI-ADRC are listed below. Gene-Environment Interaction and Neurodegenerative Disorders Angel Cedazo-Minguez In the study of signal transduction pathways involved in the pathogenesis of Alzheimer s disease (AD) and other neurodegenerative diseases, we investigate both genetic and environmental factors. Apolipoprotein E and hypercholesterolemia. Apolipoprotein E (apoe) is the main cholesterol transporter and Professor Bengt Winblad is the Director of the Karolinska Institutet Alzheimer Disease Research Center and of the Swedish Brain Power Initiative We investigate the disorder from different perspectives, emphasizing the integration of basic neuroscience research with clinical research, molecular genetics, and epidemiology. We study the generation of beta-amyloid and its relation with other pathological markers of the disease, the mechanisms of genetic and environmental risk factors for AD, the relationship between altered tau protein, and the progression of neurofibrillary changes and the characterization of genes associated with AD. We reported that apoe4 impairs several signaling cascades related to AD pathogenesis, in contrast to the positive effects seen with others apoe isoforms 17

18 Cedazo-Minguez group at the nailing of S. Akterin Ph.D. thesis. From the left: Nodi Dehvari, Laura Mateos, Angel Cedazo-Minguez, Susanne Akterin, Mónica Perez, Francisco Gil-Bea and Anna Sandebring the presence of the E4 isoform is the major risk factor for AD. High cholesterol levels in the blood also raise risk. We hypothesize that apoe4 acts in synergy with environmental factors (like hypercholesterolemia) to affect the signaling pathways involved in neurodegeneration. We were able to report differential effects of apoe isoforms on neurotoxicity, protein kinase C signaling, APP processing, and phosphoinositide hydrolysis. We also reported that a high cholesterol diet combined with a lack of functioning apoe induces tau hyperphosphorylation. Thioredoxin and glutaredoxin functions in AD. Oxidative stress (OS) is one of the pathological events occurring in AD. The amyloid-ß peptide (Aß) induces OS and neuronal apoptosis. Glutaredoxin-1 (GRX1) and thioredoxin-1 (TRX1) modulate the redox homeostasis and inhibit the apoptosis signal-regulating kinase (ASK1). We found that TRX1 levels were decreased in AD brains and showed that Aß neurotoxicity was mediated by GRX1 and TRX1 oxidations and ASK1 activation. The deregulation of GRX1 and TRX1 antioxidant systems could be critical to AD pathogenesis. Presenilin 1 modulation of acetylcholine muscarinic receptor signaling. Mutations in presenilin 1 (PS1) cause familial cases of AD. These mutations increase the production of the longer forms of Aß and affect calcium homeostasis, increasing neuronal susceptibility to apoptosis. Cholinergic signaling regulates calcium in neurons, and it is impaired in AD. We found a new physiological function of PS1 that involved the regulation of acetylcholine muscarinic receptor signaling via phopholipase C, endoplasmic reticulum calcium release, and the modulation of protein kinase C (PKC) and extracellular regulated kinase (ERK). This function is impaired in PS1 mutations that cause AD. The biological functions of Parkin and PINK1. Mutations in parkin and in PTEN-induced putative kinase 1 (PINK1) cause familial recessive forms of parkinsonism by unknown mechanisms. We are investigating the biological function of these proteins as well as the effects of their mutations. Akterin S, Cowburn RF, Miranda-Vizuete A, Jiménez A, Bogdanovic N, Winblad B, Cedazo-Minguez A. Involvement of glutaredoxin-1 and thioredoxin-1 in beta-amyloid toxicity and Alzheimer s disease. Cell Death Differ. 2006;13: Cedazo-Mínguez A. Apolipoprotein E and Alzheimer s disease: molecular mechanisms and therapeutic opportunities. J Cell Mol Med. 2007;11: Chuan YC, Pang ST, Cedazo-Minguez A, Norstedt G, Pousette A, Flores-Morales A. Androgen induction of prostate cancer cell in vasion is mediated by ezrin. J Biol Chem. 2006;281: Dehvari N, Cedazo-Minguez A, Isacsson O, Nilsson T, Winblad B, Karlström H, Benedikz E, Cowburn RF. Presenilin dependence of phospholipase C and protein kinase C signalling. J. Neurochem. 2007;102: Rahman A, Akterin S, Flores-Morales A, Crisby M, Kivipelto M, Schultzberg M, Cedazo-Mínguez A. High cholesterol diet induces tau hyperphosphorylation in apolipoprotein E deficient mice. FEBS Lett. 2005;579:

19 Genetics of Neurodegenerative Diseases. Novel Drug Targets: Genomics Caroline Graff Genetic studies strive to provide novel information regarding the impact of genes on risk for neurodegenerative diseases in general and AD in particular. Information will be translated into clinical practice where applicable through genetic counseling for dementias at the Memory Clinic, Karolinska University Hospital at Huddinge. We collaborate closely with the neuropathology department, the epidemiology section, and the Swedish Brain Power initiative. We are particularly interested in the genetics of familial forms of dementia such as familial Alzheimer s disease and frontotemporal dementias. Mutation screening in Lou Gehrig s disease (ALS), frontotemporal dementia (FTD), and AD. Swedish patients suffering from ALS, FTD, and AD can be characterized with respect to mutations in the known disease genes. The biochemical properties of the identified mutations will be analyzed in functional studies. We use clinical data and neuropathological findings to perform genotype-phenotype correlation studies. Eventually, clinical practice will provide guidelines on the likelihood of a particular patient having a heritable form of the disease. Case-control association studies in AD Candidate gene approach. We use a large case-control sample series for association studies of genes that code for proteins involved in the pathoetiology of AD. These genes may be future targets of risk prediction and early diagnostic markers. Genetic risk genes for AD and longevity-longitudinal population based samples. In close collaboration with the NVS epidemiology section, we try to understand the contribution of genes to the risk of AD and the expected lifetime in the general population. With this information, we hope the health of the Swedish population can be improved by primary intervention. If we can identify novel genes implicated in the development of AD, we may identify novel drug targets and early diagnostic tools. In KASPAC and in collaboration with Dainippon Sumitomo Pharma we run the following projects. Whole genome linkage studies of familial Alzheimer s disease. We have genotyped more than 1000 microsatellite markers in 109 Swedish families with AD in two genome-wide linkage studies. At present, we are finemapping the linked regions. Genealogical studies help us find common ancestries between the families, and we continually update the clinical status of the families. Transgenic mouse model with the human amyloid precursor protein arctic mutation (APParc). We have generated an happarc transgenic mouse model that carries the human APP gene with the E693G mutation. Behavior, memory, and neuropathological changes are studied longitudinally. The model may serve as a useful tool in drug screening and understanding the molecular mechanisms of neurodegeneration. Global gene expression analyses of fibroblast RNA in early onset dominant AD. A pattern of gene expression in fibroblasts can be used to differentiate individuals carrying AD mutations (who unequivocally will or already have developed AD) from individuals who do not carry these mutations (who have the general population risk of developing AD. In a large-scale validation study of the gene expression profile, we use fifty additional samples to develop early diagnostic tools and possibly find molecular pathways contributing to the development of the disease. Andrade J, Andersen M, Sillén A, Graff C, Odeberg J. The use of grid computing to drive data-intensive genetic research. Eur J Hum Genet. 2007;15: Belin AC, Björk BF, Westerlund M, Galter D, Sydow O, Lind C, Pernold K, Rosvall L, Håkansson A, Winblad B, Nissbrandt H, Graff C, Olson L. Association study of two genetic variants in mitochondrial transcription factor A (TFAM) in Alzheimer s and Parkinson s disease. Neurosci Lett. 2007;420: Björk BF, Katzov H, Kehoe P, Fratiglioni L, Winblad B, Prince JA, Graff C. Positive association between risk for late-onset Alzheimer disease and genetic variation in IDE. Neurobiol Aging. 2007;28: Nagasaka Y, Dillner K, Ebise H, Teramoto R, Nakagawa H, Lilius L, Axelman K, Forsell C, Ito A, Winblad B, Kimura T, Graff C. A unique gene expression signature discriminates familial Alzheimer s disease mutation carriers from their wild-type siblings. Proc Natl Acad Sci U S A. 2005;102: Sillén A, Forsell C, Lilius L, Axelman K, Björk BF, Onkamo P, Kere J, Winblad B, Graff C. Genome scan on Swedish Alzheimer s disease families. Mol Psychiatry. 2006;11: Action Mechanisms: γ-secretase and mitochondria. Maria Ankarcrona Aß generation and mitochondria play critical roles for the neuronal degeneration in Alzheimer disease (AD). γ-secretase cleavage of the amyloid precursor protein (APP) generates amyloid-ß peptides (Aß), which aggregate and form plaques in the Alzheimer brain. Other γ-secretase substrates are eg NOTCH, E- and N-cadherin,nectin and Erb-B4. The presence of different γ-secretase substrates suggest that this protease participates in several important functions in the cell. 19

20 generated in mitochondria. The reason is that incomplete mitochondrial translocation of APP leaves the Aß region outside the mitochondrial membrane, making it impossible for the mitochondrial γ-secretase complex to cleave APP. Thus the function of these complexes in mitochondria is not known, and we are currently searching for substrates and their role in AD pathology. Since Aß is not likely to be produced locally in mitochondria, the Aß detected in AD brain mitochondria has to be taken up by. We have recently studied these uptake mechanisms and shown that Aß is imported via the translocase at the outer membrane of mitochondria (TOM) import machinery. Immunoelectron microscopy of Aß1-42 localization to mitochondria in a human brain biopsy from a patient with amyloidosis. Arrows indicate ImmunoGold labelling of Aß1-42. From Hansson Petersen et al (2008) PNAS 105: The γ-secretase complex consists of at least presenilin, Nicastrin, Aph-1, and Pen-2. It is assembled in the ER- Golgi pathway and subsequently transported to the plasma membrane where the substrate cleavage occurs. However, γ-secretase and its substrates have also been identified in other cellular compartments. We have shown that active γ-secretase complexes are localized to mitochondria. Caspase-cleaved presenilin fragments are able to form active γ-secretase complexes. This suggests that Aß can be generated by cells triggered to undergo apoptosis. We hypothesize that cells triggered to die produce Aß and affect neighboring cells, by for example mitochondrial toxicity, triggering further Aß-production and cell death. Thus apoptotic cells would drive a viscous cycle leading to Aß deposition and plaque formation in AD. We are currently studying the amounts and lengths of Aß peptides produced by cells transfected either with caspase- cleaved presenilin fragments or normally processed presenilin. In collaboration with Medivation, Inc., we are working on a project aiming to elucidate the mechanisms of action for Dimebon. This drug is now in a phase III study and has previously shown positive results on AD patients in a Russian study. Our project in KASPAC focuses on the role of mitochondrial γ-secretase activity, mitochondrial Aß accumulation, and Omi/HtrA1 protease activity. Aß has been detected in mitochondria from AD brain and impairs mitochondrial functions in in vitro experiments. Even though both active γ-secretase complexes and APP are localized to mitochondria, Aß is probably not Omi/HtrA1 is a protease that is released from the mitochondrial intermembrane space upon apoptotic stimuli. In the cytoplasm, it degrades inhibitors of apoptosis proteins and promotes apoptosis. However, when inside mitochondria Omi/HtrA1can degrade misfolded proteins and thus maintain the mitochondrial function. Mutations and polymorphisms in Omi/ HtrA1 have been linked to familial forms of Parkinson disease. Here we study the function of Omi/HtrA1 in the AD brain. Behbahani H, Shabalina IG, Wiehager B, Concha H, Hultenby K, Petrovic N, Nedergaard J, Winblad B, Cowburn RF, Ankarcrona M.Differential role of Presenilin-1 and -2 on mitochondrial membrane potential and oxygen consumption in mouse embryonic fibroblasts. J Neurosci Res. 2006;84: Falkevall A, Alikhani N, Bhushan S, Pavlov PF, Busch K, Johnson KA, Eneqvist T, Tjernberg L, Ankarcrona M, Glaser E. Degradation of the amyloid beta-protein by the novel mitochondrial peptidasome, PreP. J Biol Chem. 2006;281: Hansson CA, Popescu BO, Laudon H, Cedazo-Minguez A, Popescu LM, Winblad B, Ankarcrona M. Caspase cleaved presenilin-1 is part of active gamma-secretase complexes. J Neurochem. 2006;97: Rickle A, Behbahani H, Ankarcrona M, Winblad B, Cowburn RF. PTEN, Akt, and GSK3beta signalling in rat primary cortical neuronal cultures following tumor necrosis factor-alpha and trans-4-hydroxy-2-nonenal treatments. J Neurosci Res. 2006;84: Selivanova A, Winblad B, Farmery MR, Dantuma NP, Ankarcrona M. COPI-mediated retrograde transport is required for efficient gamma-secretase cleavage of the amyloid precursor protein. Biochem Biophys Res Commun. 2006;350: Behavioral Neuroscience Abdul Mohammed Our research interest is in understanding the impact of environment, genes, and gene-environment interaction on brain anatomy, neurotrophins, and behavior during adulthood and aging. We use genetically modified mice models of CNS dysfunction to assess behavioral responses. For behavioral phenotyping of genetically 20